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EP3674304B1 - Forme cristalline d'un inhibiteur de parp-1 et son procédé de préparation - Google Patents

Forme cristalline d'un inhibiteur de parp-1 et son procédé de préparation Download PDF

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Publication number
EP3674304B1
EP3674304B1 EP18849247.4A EP18849247A EP3674304B1 EP 3674304 B1 EP3674304 B1 EP 3674304B1 EP 18849247 A EP18849247 A EP 18849247A EP 3674304 B1 EP3674304 B1 EP 3674304B1
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Prior art keywords
crystal form
formula
cancer
compound
water
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Not-in-force
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EP18849247.4A
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English (en)
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EP3674304A1 (fr
EP3674304A4 (fr
Inventor
Wenhai LI
Quanliang ZHANG
Zhenjun QIU
Zhengming Li
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a crystal form of PARP-1 inhibitor and a preparation method therefor.
  • PARPs poly (ADP ribose) polymerases
  • PARP-1 is one of the important members of the PARP family and is considered as a promising target for exploring new cancer treatments.
  • ZL201180003990.9 disclosed a new PARP inhibitor, 4-[[3-[[2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-yl]carbonyl]-4-fluorophenyl]methyl-1(2H)-phthalazinone (formula I).
  • the compound can inhibit the activity of PARP enzyme significantly in vitro, and it can inhibit tumor growth significantly in nude-mouse transplanted tumor model. Meanwhile, toxicological data in rats and dogs also confirmed that the compound has a corresponding safety.
  • the specific structure is as follows:
  • the polymorphy refers to the phenomenon that solid substances exist in two or more different spatial arrangements, which have different physical and chemical properties.
  • the bioavailability of the same pharmaceutical may also differ among different crystal forms due to the different arrangements.
  • the present invention provides a crystal form A of 4-[[3-[[2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine-7-yl]carbonyl]-4-fluorophenyl]methyl-1(2H)-phthalazinone (formula I), which is characterized by an X-ray powder diffraction pattern expressed by a diffraction angle of 2 ⁇ obtained by using Cu-Ka radiation, which has characteristic peaks at 9.58, 15.25, 17.09, 18.63, 21.11, 22.79, 23.99, 24.23, 27.26, 28.97,
  • the crystal form A of the compound of formula I is characterized by the X-ray powder diffraction pattern expressed by a diffraction angle of 2 ⁇ obtained by using Cu-Ka radiation, which has characteristic peaks at 9.58, 15.25, 17.09, 18.29, 18.63, 19.18, 21.11, 22.79, 23.99, 24.23, 27.26, 28.97.
  • the crystal form A of the compound of formula I is characterized by the X-ray powder diffraction pattern expressed by a diffraction angle of 2 ⁇ obtained by using Cu-Ka radiation, which has characteristic peaks at 9.58, 10.22, 13.00, 15.25, 17.09, 18.29, 18.63, 19.18, 21.11, 22.79, 23.99, 24.23, 27.26, 28.97.
  • the crystal form A of the compound of formula I is characterized by the X-ray powder diffraction pattern expressed by a diffraction angle of 2 ⁇ obtained by using Cu-Ka radiation, which has characteristic peaks at 9.58, 10.22, 12.76, 13.00, 15.25, 15.82, 16.11, 16.90, 17.09, 18.29, 18.63, 19.18, 20.65, 21.11, 22.79, 23.99, 24.23, 27.26, 28.97. Further, the X-ray powder diffraction pattern of the crystal form A is shown in Figure 1 .
  • the present invention also provides a preparation method for the crystal form A of the compound of formula I, which comprises:
  • the solvent (II) described in this method may be selected from but not limited to at least one of butanone, tetrahydrofuran, acetone, methanol, ethanol, water acetonitrile, and ethyl acetate, preferably from butanone, tetrahydrofuran, acetone, methanol, ethanol/water, tetrahydrofuran/water, acetone/water, acetonitrile, acetonitrile/water, ethyl acetate, butanone/water; the volume of the solvent (II) used may be 1-100 times of the weight of formula I, preferably 5-70 times, and may be 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58
  • the crystallization temperature described in this method may be 0-40°C, and in a non-limited embodiment, the crystallization temperature may be 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40°C, preferably be 10-30°C.
  • the present invention also provides a solid pharmaceutical composition, which is prepared from the crystal form A of the aforementioned compound of formula I.
  • the pharmaceutical composition may also contain one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present invention may be further prepared into an injection solution or a solid preparation with an intermediate preparation, and the solid preparation is selected from but not limited to tablets, pills, granules, lyophilized powder injections or capsules.
  • the excipient in the solid preparation is well known to or can be determined by those skilled in the art, and is selected from but not limited to at least one of a disintegrant, a filler, a binder, and a lubricant; the excipient in the injection solution is selected from but not limited to at least one of a non-toxic physiologically acceptable liquid carrier, such as physiological saline, water for injection, 5% glucose injection solution, glucose sodium chloride injection solution, pH regulator or preservative.
  • a non-toxic physiologically acceptable liquid carrier such as physiological saline, water for injection, 5% glucose injection solution, glucose sodium chloride injection solution, pH regulator or preservative.
  • the present invention also provides a use of the crystal form A of the compound of formula I or the aforementioned pharmaceutical composition in the preparation of a medicament for inhibiting PARP, or a use in the preparation of a medicament that is used as an adjuvant or for making tumor cells sensitive to ionizing radiation or chemotherapy in the treatment of cancer, the cancer is selected from breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, liver cancer or colon cancer.
  • the aforementioned medicament may be used in combination with a therapeutically effective dose of pharmaceuticals selected from temozolomide, doxorubicin, cisplatin, carboplatin, or dacarbazine.
  • the “differential scanning calorimetry or DSC” in the present invention refers to that during the heating process or constant temperature process of the sample, the temperature difference and heat flow difference between the sample and the reference are measured to characterize all physical changes and chemical changes related to the thermal effects, so as to obtain the phase transition information of the sample.
  • the "2 ⁇ or 2 ⁇ angle" in the present invention refers to a diffraction angle, ⁇ is a Bragg angle, with the unit as ° or degree.
  • the error range of 2 ⁇ in the present invention may be ⁇ 0.5, and may also be ⁇ 0.1, ⁇ 0.2, ⁇ 0.3, ⁇ 0.4, ⁇ 0.5.
  • the "beat” described in the present invention refers to a method for purifying by utilizing the characteristics of poor solubility of a substance in a solvent but good solubility of the impurities in the solvent. Beating purification can remove color, change crystal form or remove a small amount of impurities.
  • the temperature of drying in the present invention is generally 20°C-100°C, preferably 30°C-70°C, and the drying can be performed under atmospheric pressure or under reduced pressure. Preferably, the drying is performed under reduced pressure.
  • interplanar crystal spacing or interplanar spacing (d value) in the present invention refers to that in the space lattice, three non-parallel unit vectors a, b, and c that each connects adjacent two lattice points are selected, which divide the lattice into juxtaposed parallelepiped units, called the interplanar crystal spacing.
  • the space lattice is divided by the connected lines between the determined parallelepiped units, to obtain a set of linear grids, which are called space lattice or crystal lattice.
  • Lattice and crystal lattice reflect the periodicity of the crystal structure with geometric points and lines, respectively. Different crystal planes have different interplanar distances (that is, the distance between two adjacent parallel crystal planes); the unit is ⁇ or angstrom.
  • Example 1 preparation of crystal form A
  • the DSC melting peak of the sample is around 244.4°C, and the initial melting temperature is 242.0°C.
  • the characteristic peak positions are shown in Table 1 below: Table 1 Peak number 2 ⁇ value [° or degree] D[ ⁇ ] Relative intensity [%] 1 8.78 10.06 7.1 2 9.58 9.22 100.0 3 10.22 8.65 19.1 4 12.40 7.13 7.2 5 12.76 6.93 12.5 6 13.00 6.80 17.8 7 13.19 6.71 8.3 8 15.25 5.81 68.6 9 15.82 5.60 10.9 10 16.11 5.50 10.6 11 16.90 5.24 16.7 12 17.09 5.18 24.2 13 17.62 5.03 3.0 14 18.29 4.85 19.3 15 18.63 4.76 49.7 16 19.18 4.62 19.7 17 19.93 4.45 3.1 18 20.65 4.30 13.9 19 21.11 4.21 29.0 20 21.87 4.06 2.0 21 22.79 3.90 42.1 22 23.99 3.71 37.5 23 24.23 3.67 43.6 24 24.97 3.56 4.0 25 25.26 3.52 6.4 26 25.71 3.46 8.
  • Example 8 preparation of crystal form A
  • Example 2 The sample of Example 1 was subjected to an accelerated stability test (40°C, relative humidity of 75%) for 6 months and then sent to XRD for testing, and compared with the original data to confirm whether the crystal form changed. The results are shown in Table 2.
  • the XRPD pattern of crystal form A of the compound of formula I after 6 months of the accelerated stability test (40°C, relative humidity of 75%) is shown in Figure 3 .
  • the comparative XRPD pattern of crystal form A of the compound of formula I after accelerated stability test is shown in Figure 4 .
  • Table 2 Comparison of XRD data of the sample and the sample after 6 months of accelerated stability test Serial Number
  • Example 1 XRD-2 ⁇ value XRD-D[ ⁇ ] 0 month 6 months 0 month 6 months 1 9.56 9.58 9.24 9.22 2 10.22 10.20 8.65 8.66 3 15.20 15.21 5.82 5.82 4 15.80 15.80 5.60 5.61 5 17.08 17.09 5.19 5.19 6 18.58 18.53 4.77 4.78 7 20.60 20.63 4.31 4.30 8 21.06 21.11 4.22 4.21 9 22.76 22.78 3.90 3.90 10 24.18 24.23 3.68 3.67 11 27.18 27.25 3.28 3.27 12 28.90 28.96 3.09 3.08
  • the crystal form of the sample did not change after being placed under accelerated stability test conditions (40°C, relative humidity of 75%) for 6 months, indicating that the crystal form is stable and suitable for drug development.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (12)

  1. Forme cristalline A du composé répondant à la formule I, dans laquelle la figure de diffraction des rayons X sur poudre, exprimée par un angle de diffraction de 2θ et obtenue en utilisant des rayons Cu-Kα, présente des reflets caractéristiques à 9,58, 15,25, 17,09, 18,63, 21,11, 22,79, 23,99, 24,23, 27,26, 28,97 :
    Figure imgb0005
  2. Forme cristalline A selon la revendication 1, dans laquelle la figure de diffraction des rayons X sur poudre, exprimée par un angle de diffraction de 2θ et obtenue en utilisant des rayons Cu-Kα, présente des reflets caractéristiques à 9,58, 15,25, 17,09, 18,29, 18,63, 19,18, 21,11, 22,79, 23,99, 24,23, 27,26, 28,97.
  3. Forme cristalline A selon la revendication 1 ou 2, dans laquelle la figure de diffraction des rayons X sur poudre, exprimée par un angle de diffraction de 2θ et obtenue en utilisant des rayons Cu-Kα, présente des reflets caractéristiques à 9,58, 10,22, 13,00, 15,25, 17,09, 18,29, 18,63, 19,18, 21,11, 22,79, 23,99, 24,23, 27,26, 28,97.
  4. Forme cristalline A selon la revendication 1 ou 2, dans laquelle la figure de diffraction des rayons X sur poudre, exprimée par un angle de diffraction de 2θ et obtenue en utilisant des rayons Cu-Kα, présente des reflets caractéristiques à 9,58, 10,22, 12,76, 13,00, 15,25, 15,82, 16,11, 16,90, 17,09, 18,29, 18,63, 19,18, 20,65, 21,11, 22,79, 23,99, 24,23, 27,26, 28,97.
  5. Forme cristalline A selon la revendication 1, dans laquelle la figure de diffraction des rayons X sur poudre obtenue en utilisant des rayons Cu-Kα est montrée dans la figure 1.
  6. Procédé de préparation pour la forme cristalline A selon l'une quelconque des revendications 1-5, comprenant les étapes consistant à
    (a) ajouter du 4-[[3-[[2-(trifluorométhyl)-5,6,7,8-tétrahydro-[1,2,4]triaz-olo[1,5-α]pyrazine-7-yl]carbonyl]-4-fluorophényl]méthyl-1(2H)-phtalazin-one (formule I) à un solvant (I), dissoudre, filtrer, concentrer à sec, dans lequel ledit solvant (I) est choisi parmi au moins l'un de butanone, dichlorométhane, acétate d'éthyle, et tétrahydrofuranne,
    (b) ajouter un solvant (II), dissoudre le solide susmentionné en agitant ou en chauffant et agitant pour cristallisation, ou ajouter un solvant (II), chauffer et chauffer à reflux pour former une pâte, agiter et refroidir,
    (c) filtrer pour obtenir le cristal du composé répondant à la formule I.
  7. Procédé de préparation selon la revendication 6, dans lequel ledit solvant (I) est choisi parmi au moins l'un de butanone, tétrahydrofuranne, acétone, méthanol, éthanol, eau, acétonitrile, et acétate d'éthyle, de préférence parmi butanone, tétrahydrofuranne, acétone, méthanol, éthanol/eau, tétrahydrofuranne/eau, acétone/eau, acétonitrile, acétonitrile/eau, acétate d'éthyle, butanone/eau.
  8. Composition pharmaceutique contenant un composé de formule I selon l'une quelconque des revendications 1 à 4, sous forme cristalline A
  9. Composition pharmaceutique selon la revendication 8, contenant en outre un ou plusieurs excipients pharmaceutiquement acceptables.
  10. Forme cristalline A du composé répondant à la formule I selon l'une quelconque des revendications 1-5 ou composition pharmaceutique selon la revendication 8 ou 9 à utiliser dans le traitement de cancer comme adjuvant ou pour sensibiliser des cellules de tumeur au rayonnement ionisant ou à la chimiothérapie.
  11. Forme cristalline A du composé répondant à la formule I selon l'une quelconque des revendications 1-5 ou composition pharmaceutique selon la revendication 8 ou 9 à utiliser dans le traitement de cancer, dans lequel ledit cancer est choisi parmi le cancer du sein, le cancer des ovaires, le cancer du pancréas, le cancer de la prostrate, le cancer du rectum, le cancer du foie, ou le cancer du côlon.
  12. Forme cristalline A du composé répondant à la formule I, ou composition pharmaceutique à utiliser selon la revendication 10 ou 11, dans laquelle la forme cristalline A du composé répondant à la formule I ou la composition pharmaceutique est utilisée en outre en combinaison avec une dose thérapeutiquement effective d'agents pharmaceutiques choisis parmi le témozolomide, le doxorubicin, le cisplatine, le carboplatine, ou la dacarbazine.
EP18849247.4A 2017-08-24 2018-08-23 Forme cristalline d'un inhibiteur de parp-1 et son procédé de préparation Not-in-force EP3674304B1 (fr)

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CN201710737513 2017-08-24
PCT/CN2018/101875 WO2019037753A1 (fr) 2017-08-24 2018-08-23 Forme cristalline d'un inhibiteur de parp-1 et son procédé de préparation

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EP3674304A1 EP3674304A1 (fr) 2020-07-01
EP3674304A4 EP3674304A4 (fr) 2020-12-16
EP3674304B1 true EP3674304B1 (fr) 2022-04-13

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US (1) US11180505B2 (fr)
EP (1) EP3674304B1 (fr)
JP (1) JP2020531522A (fr)
CN (1) CN110914272A (fr)
AU (1) AU2018320562B2 (fr)
CA (1) CA3073613A1 (fr)
ES (1) ES2915830T3 (fr)
MX (1) MX2020002046A (fr)
MY (1) MY197303A (fr)
TW (1) TWI765086B (fr)
WO (1) WO2019037753A1 (fr)

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US10703728B1 (en) * 2019-06-18 2020-07-07 Scinopharm Taiwan, Ltd. Crystalline form of olaparib and a process for preparing the same
CN115650988B (zh) * 2022-10-27 2024-09-13 江苏恒瑞医药股份有限公司 一种parp抑制剂的制备方法
TW202421139A (zh) * 2022-11-23 2024-06-01 大陸商江蘇恆瑞醫藥股份有限公司 一種含氮雜環類化合物的可藥用鹽、晶型及製備方法

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UY30639A1 (es) * 2006-10-17 2008-05-31 Kudos Pharm Ltd Derivados sustituidos de 2h-ftalazin-1-ona, sus formas cristalinas, proceso de preparacion y aplicaciones
WO2009025784A1 (fr) 2007-08-21 2009-02-26 Merck & Co., Inc. Composés hétérocycliques en tant qu'inhibiteurs de dipeptidylpeptidase-iv pour le traitement ou la prévention des diabètes
CN102372706A (zh) * 2010-08-09 2012-03-14 江苏恒瑞医药股份有限公司 酞嗪酮类衍生物、其制备方法及其在医药上的应用
CN102372716A (zh) * 2010-08-09 2012-03-14 江苏恒瑞医药股份有限公司 酞嗪酮类衍生物、其制备方法及其在医药上的应用
JP5808818B2 (ja) * 2010-11-25 2015-11-10 ラツィオファーム・ゲーエムベーハー アファチニブの新規塩及び多形形態
CN105461697A (zh) * 2014-04-29 2016-04-06 中国医学科学院药物研究所 喹唑啉酮类parp-1抑制剂及含有它们的组合物和抗肿瘤用途
US20170204067A1 (en) * 2016-01-14 2017-07-20 Scinopharm Taiwan, Ltd. Crystalline forms of olaparib and manufacturing processes therefor

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AU2018320562B2 (en) 2022-09-01
US20200291031A1 (en) 2020-09-17
EP3674304A1 (fr) 2020-07-01
RU2020110106A3 (fr) 2021-12-24
ES2915830T3 (es) 2022-06-27
MX2020002046A (es) 2020-09-17
TWI765086B (zh) 2022-05-21
CN110914272A (zh) 2020-03-24
MY197303A (en) 2023-06-12
EP3674304A4 (fr) 2020-12-16
US11180505B2 (en) 2021-11-23
CA3073613A1 (fr) 2019-02-28
JP2020531522A (ja) 2020-11-05
WO2019037753A1 (fr) 2019-02-28
TW201912646A (zh) 2019-04-01
RU2020110106A (ru) 2021-09-14
AU2018320562A1 (en) 2020-03-12

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